Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof

Definitions

• Anticoagulants and antithrombotic agents are a group of compounds with diversified pharmacological actions which are used in a variety of clinical thrombotic disorders.
• Thrombotic disorders are generally divided into venous thromboses and arterial occlusive disorders. Venous thrombosis of the lower extremities is important, because it can cause pulmonary embolisms which may be fatal.
• "Heparin” and "Warfarin” are commonly used in clinical medicine for the prevention and treatment of deep venous thromboses and pulmonary embolisms. Their main pharmacological actions are to inhibit or interrupt blood coagulation activity.
• Platelets play an important part in arterial thrombosis. Drugs which inhibit platelet aggregation are generally regarded as potentially useful for the prophylactic therapy of arterial thrombotic disorders, including, for example, strokes, myocardial infarctions 'and peripheral vascular disease. Despite the availability of many agents which possess platelet anti-aggregatory properties, only a few are currently under clinical trial (for example "Aspirin”, dipyridamole and sulphinpyrazone). None of these agents exhibits unequivocal efficacy. Compounds with more specific pharmacological actions are urgently sought in order to provide better medical care for patients with these serious disorders.
• An anticoagulant is a substance which inhibits coagulation of the blood.
• a platelet anti-aggregatory agent is a substance which inhibits platelet aggregation.
• an antithrombotic agent is a substance which inhibits the formation or development of a thrombus (or thrombosis).
• thrombus or thrombosis
• the term "thrombus” or its equivalent includes the term “embolus”, unless otherwise specifically indicated.
• an antithrombotic agent in the presence of mammalian blood or appropriately-prepared plasma, may display anticoagulant activity and/or platelet anti-aggregatory activity.
• Examples of clinical thrombotic conditions include stroke (as a cerebral vascular thrombosis), myocardial infarction (coronary artery disease), peripheral vascular disease, cardiac valve replacement, deep vein thrombosis and pulmonary embolism.
• a class of active agents has now been discovered the members of which, when orally ingested and/or injected, produce amelioration of a thrombotic condition in mammals (including man), when used in anti-thrombotically-effective amounts as described below.
• 81302950.1 is a pharmaceutical composition which contains at least one carrier substance and, as the active treating agent, at least one organic compound which in aqueous solution furnishes one or both of bisulphite ions and sulphite ions, the composition having the ability to prolong prothrombin time in human plasma by at least 1.5 times and the ability to prolong blood partial thromboplastin time in human plasma by at least 2.0 times, each as compared to a control using a final concentration of such compound of 0.5 millimolar.
• the active treating agent preferably is selected from:
• the present invention is directed to the use of certain bisulphite and sulphite pharmaceutical compositions as antithrombotic, anticoagulant and platelet anti-aggregatory agents in mammalian medicine (including human medicine). These agents are believed to be usable in both arterial and venous thrombotic conditions.
• the present invention is directed to a method for the control of and/or the prevention of an embolus or a thrombus in man by oral ingestion and/or by injection or the use of suppositories of a pharmaceutically-effective amount of one or more compounds comprising the active agents of this invention.
• the present invention provides symptomatic and objective improvement in thrombotic (including cardiovascular) disease conditions, for example, abnormal coagulation or intravascular thrombosis, in man.
• symptomatic improvement means an improvement in a patient's subjective symptoms (e.g., as reported by the patient).
• objective improvement means a measurable change in a patient's condition.
• a pharmaceutical composition for treating an actual or incipient thrombotic condition in a mammal is characterised in that it contains at least one carrier substance and, as the active treating agent, at least one inorganic compound which in aqueous solution furnishes one or both of bisulphite ions and sulphite ions, such compositions having the ability to prolong prothrombin time in human plasma by at least 1.5 times and the ability to prolong blood partial thromboplastin time in human plasma by at least 2.0 times, each as compared to a control using a final concentration of such compound of 0.5 millimolar.
• the active treating agent is sodium bisulphite.
• a process of preparation of a pharmaceutical composition of this invention is characterized in that the carrier substance, the active treating agent and any other components are combined in the sterile state and under sterile conditions so that an equilibrium reaction product of the formula is at least partly formed and portions of the resultant composition are optionally packaged in dosage unit form.
• a method of treating a thrombotic condition in a mammal is characterized by administering to such mammal an antithrombotically-effective amount of at least one inorganic compound comprising an active treating agent as defined above.
• this invention concerns a process for treating a human or other mammal wherein there is introduced orally and/or by injection into such mammal a pharmaceutically-effective amount of an active agent of this invention as an antithrombotic agent.
• Sulphite and/or bisulphite anions do not normally occur in human tissues or blood, so far as is now known.
• arterial thrombosis is diagnosable, for example, by clinical manifestations, by arteriography and, recently, by an indium 111 platelet labelling technique (see, for example, the article entitled "Differential Effects of Two Doses of Aspirin on Platelet-Vessel Wall Interaction In Vivo" by K.K. Wu et al being published in the Journal of Clinical Investigation, August, 1981).
• a thrombosis is detectable, for example, from a patient's conditions symptomatically perceivable by a skilled medical practitioner and well known to the art of medicine.
• various methods are available, including venography, impedance plethysmo- graphy, doppler ultrasound and the 125 I-fibrinogen test (see, for example, the articles by Kakkar, "Archives of Surgery", 104, page 152 (1972) and by Kelton, J.G. et al, Journal of Clinical Investigation, Vol. 62, pgs. 892-895, (1978)).
• the present invention does not contemplate feeding a normal patient (that is, one not suffering from a thrombotic condition) an active agent of this invention at a pharmaceutically-effective dosage as indicated herein.
• thrombotic condition means both:
• thrombus or "incipient thrombotic condition”, as used herein, is a condition which can exist in a patient who is predisposed to the development of a thrombotic condition.
• diabetes mellitus and hyperlipidemia are conditions which predispose a patient to arterial thrombosis.
• surgery, trauma and bed rest for example, predispose a patient to venous thrombosis.
• thrombotic condition including an actual thrombus in a patient.
• the practice of this invention in vivo involves introducing into the blood of a patient such as a human, the equivalent of 1 to 100 milligrams per kilogram of mammal body weight (including human) per day, though larger or smaller dosage rates may be employed, if desired, within the scope of this invention.
• the exact amount or dose in any given case is selected to be sufficient and appropriate for achieving a desired antithrombotic effect.
• such an introduction may be commenced at a dosage rate within the range above indicated as soon as a thrombotic condition (or a thrombus) is found in a patient.
• an especially preferred dosage rate is 20 to 50 mg/kg per day.
• at least two or three spaced doses per day are given, each such dose being conveniently administered around a meal-time. Any convenient dosage arrangement can be employed.
• the active agent can be directly introduced by injection into the patient, if desired, such as intravenously, intramuscularly or subcutaneously.
• an active agent is directly introduced, it is preferably dissolved in an aqueous medium, the total amount of active agent introduced into such medium preferably being within the range from 1 to 11. weight percent (based on the total solution weight). Distilled water is preferred as the aqueous medium.
• conventional (standardized) aqueous media can be used as vehicles for such introduction; for example, standard saline solutions can be used as vehicles.
• the dosage rate is preferably adjusted to a value which is sufficient to disrupt platelet function and/or coagulation factors and thereby achieve a desired antithrombotic effect.
• An active agent of this invention is characteristically capable of exhibiting platelet aggregation both in vitro and in vivo. Also, such an active agent is characteristically capable of lengthening both PT (prothrombin time) and PTT (blood partial thromboplastin time) in vitro,
• PT prothrombin time
• PTT blood partial thromboplastin time
• the dosage rate of the active' agent is currently believed to be related to the resulting effects upon blood factors, such as inhibition of platelet aggregation. Consequently, under this preferred procedure, use of an active agent at a suitable dose for an individual patient ameliorates that patient's thrombotic condition.
• Selected blood parameters of a patient are preferably determined before dosing with an active agent is started, when time permits.
• dosage rate adjustment is made while administration of an active agent is continuing.
• the amount of adjustment is determinable by comparing a patient's measured values during administration of active agent to desired values (such as the patient's own corresponding starting values or normal species, e.g. human, values). Inhibition of platelet aggregation can-be used for such measurements. Then, the deviation, if any, from the patient's measured values is compared to the desired values (the patient's starting values or normal species values, for example). Then, a change in dosage rate may be made to correct any deviation so determined.
• platelet aggregation is dependent upon the particular agent used for stimulation. For example, when adenosine diphosphate (ADP) at 3 micromolar concentration is employed, platelet aggregation values fall typically in the range from 50% to 100% of light transmission.
• Other stimulation agents include collagen, epinephrine and arachidonic acid.
• normal PT values fall in the range from 11 to 13 seconds, while normal PTT values fall in the range from 25 to 41 seconds. If PT values and/or PTT values could be measured in a given patient, for the purpose of. achieving a desired antithrombotic effectiveness, it is currently estimated that a lengthening of PTT value to 1.5 to 2 times a PTT value in such normal range in a given starting patient is appropriate or suitable for antithrombotic effectiveness, which amounts to a PTT value for a given patient of 45 to 60 seconds; such an estimate is consistent, for example, with the lengthened PTT.values achieved in the human use of heparin, sometimes employed previously as an antithrombotic agent.
• a lengthening of PT value to 2.0 times a PT value in such normal range in a given starting patient is appropriate or suitable for antithrombotic effectiveness, which amounts to a PT value for a given patient of 22 to 26 seconds; such an estimate is consistent, for example, with the lengthened PT values achieved in the human use of coumadin (Warfarin), sometimes employed previously as an antithrombotic agent.
• the active agents of the present invention contrary to such prior art agents, suprisingly appear to affect both PT and PTT values in vitro in a given patient. The mechanism by which the present active agents work is apparently substantially different from, and not comparable to, the prior art agents. Study and evaluation of the active agents of this invention continues.
• the active agents of the present invention appear to affect both blood coagulation factors and platelet aggregation.
• measurements of blood factors are carried out periodically, such as every 3 to 7 days, on a patient undergoing treatment under the practice of this invention.
• An active agent can be given orally, in the form of a capsule or tablet, or in the form of a solution (e.g. aqueous). Also, an active agent can be injected in the form of an aqueous solution.
• a particularly preferred antithrombotic field of use is in post-operative treatment, as when arteries or deep veins may be involved in, or threatened by, a thrombotic condition.
• the venous system in the lower extremities consists of superficial and deep veins. Because of the manner in which the deep veins interconnect and supply blood to the heart and lungs, a thrombus occurring in the deep veins, but not in the superficial veins, can become the source of a blood clot which is moved through the veins and becomes lodged in the lungs, resulting in a pulmonary embolus, which can have obvious catastrophic effects (including causing death).
• Examples of deep veins include the iliac, the femoral, the popliteal and the calf veins. The prevention of pulmonary emboli following surgery affecting the deep veins in the lower extremities is a significant medical problem.
• One solution to this problem is to prevent thrombi from occurring and/or developing in deep veins.
• active agents of this invention appear to be well suited.
• an aqueous solution of 1 to 10 percent by weight of an active agent of this invention is prepared. Then, this solution is orally consumed by a human or is injected at a total (or accumulated) dosage rate ranging from 1.0 to 50 mg per kg of body weight per day, more preferably in the form of at least two spaced doses per day, and still more preferably in the form of at least three spaced doses per day, each dose preferably being taken around a meal time.
• solid or encapsulated active agents may be orally consumed.
• the water used in such a solution is preferably purified (e.g., filtered, deionized or distilled). After preparation, the solution is preferably stored in a closed container to reduce oxidation.
• Such an aqueous solution can be directly used in carrying out this invention, in which case such a solution can be dispensed dropwise or it can be encapsulated, for instance, and used as measured dosage units, as desired.
• aqueous solution containing 5 weight percent of sodium bisulphite can be injected into a patient, or it can be directly consumed by a patient as drops (e.g. from 5 to 9 drops per meal for each of the two or three meals eaten by such patient per day, depending upon an individual patient's body weight).
• Symptomatic improvement in varicose veins and in haemorrhoids may be observable when using an active agent of this invention.
• aqueous solutions of sulphur dioxide display a capacity to lengthen PT and PTT values at least to the extent indicated above
• aqueous solutions of sulphur dioxide can be used in combination with, e.g. in admixture with, aqueous solutions of compounds forming the active treating agents of this invention.
• One preferred aqueous composition is suitable for the treatment of thrombotic conditions selected from (a) deep vein thrombosis, (b) incipient deep vein thrombosis due to surgery, trauma, prolonged bed rest or obstetrics, (c) arterial thrombosis and (d) incipient arterial thrombosis due to diabetes mellitus or hyperlipidemia.
• a preferred method for treating a thrombotic condition in a mammal (including man), by the present invention is characterized by:
• the present invention can also be regarded as a method which can be practised in vivo or in vitro for inhibiting blood coagulation factors and for inhibiting platelet aggregation involving adding to blood and/or plasma derived from such blood an active agent of this invention.
• a solution of sodium bisulphite was prepared by dissolving pharmaceutical grade (U.S.P.) powdered sodium metabisulphite in distilled water at room temperature to form a 1% by weight solution.
• This solution was put into plastics squeeze bottles, each having a volume of 50-52 ml. Each bottle was provided with a cap permitting dropwise dispensing of the solution from the bottle at an estimated rate of 15 drops per ml.
• Example A was repeated, except that a 2.5% by weight solution was formed.
• Example A was repeated, except that a 5% by weight solution was formed.
• Example A was repeated, except that a 7.5% by weight solution was formed.
• Example A was repeated except that a 10% by weight solution of potassium metabisulphite was prepared.
• a solution of sulphur dioxide in water was prepared by bubbling a purified grade of sulphur dioxide through distilled water at room temperature to form a 2% by weight aqueous solution. The product was then titrated with alkali using phenolphthalein to verify its concentration.
• a 1% by weight aqueous solution of sodium metabisulphite was prepared as in Example A.
• Purified S0 2 gas was then bubbled through the solution to give a concentration of S0 2 in the solution of 1% by weight.
• That sodium bisulphite is a platelet anti-aggregatory agent is shown by using a platelet aggregometer based on the technique of Born (above cited). It is found that this material in a concentration of 1 millimole (mM) abolishes platelet aggregation in human platelet-rich plasma occluded by optimal concentration of ADP, collagen, epinephrine, and arachidonic acid.
• mM millimole
• Sodium bisulphite was evaluated as an antithrombotic agent in vivo using the indium-111 platelet labelling technique in rabbits (see the Wu et al article above cited). The material was administered by intravenous injection (72.80 milligrams per kilogram of animal body weight).
• the findings indicate that the active agent reduces accumulation of platelet thrombus at the damaged vessel wall by 70%.
• the anti-venous thrombotic effect of sodium bisulphite was evaluated in rabbits by using the I 125 fibrinogen technique described above.
• Each rabbit was continuously infused with aqueous sodium bisulphite solution at the rate of 460 mg/kg per hr. (2.97 grams) (animal body weight 2.3 kg).
• the animal was sacrificed and the radioactive fibrinogen accumulated in the damaged jugular vein was determined.
• the radioactivity in the contra-lateral (undamaged) jugular vein was also determined, to serve as a control.
• another rabbit was subjected to the same procedure, but was given only a standard sodium chloride solution, as a control. It was found to have 7 times as much radioactivity as the counterpart infused with sodium bisulphite.
• sodium bisulphite shows a definite positive effect in decreasing thrombus formation in the jugular vein.
• mice Five rats, each in a separate cage, were given a bait containing 0.5 percent by weight of sodium bisulphite.
• the bait consisted of cracked grains (wheat, corn, millet and corn meal).
• the amounts of bait eaten were summarized for an eleven day period.
• the first day determination of PT showed that three of the rats had an increase of PT values with no apparent change in PTT (TABLE VII).
• each patient was provided with a bottle of Solution D, unless otherwise noted, and was instructed to dose himself (or herself, as the case may be) from the bottle so provided at the rate of seven drops to be taken orally with each of his (her) three daily meals.
• the contents of one such bottle were thus gradually consumed by an individual patient, another was provided.
• Samples of about 4 cc each of his blood were prepared. To each of these was added about 10 drops of a 10 weight percent solution of sodium bisulphite in distilled water. Each sample was then sealed into a glass vial. After about 2, years of storage at ambient temperatures, these blood samples have not coagulated.
• this same man Before taking this medication, this same man also had a blood cholesterol value which oscillated between 200 and 220 mg %. After about 5 years of taking this medication as described above, this man was found to have a blood cholesterol value of about 144 mg %, which value this man continues t Q keep through continued treatment by sodium bisulphite solutions as described above.
• Solution D was substituted for Solution C at about the dose rate (7 drops with each of three daily meals). Physiotherapy is being used. Use of Solution C has not improved or changed the damage to his sciatic nerve, but walking has become easier.

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